Project summary: Ovarian cancer is the fifth leading cause of cancer death among women. It is known that there is an increased risk of ovarian cancer in women who are on estrogen-only hormone replacement therapy and possible decreased risk in women who take the contraceptive pill, lending support to the idea that steroid hormones are playing a role in the etiology of ovarian cancer. This project is designed to clarify the role of estrogen and its receptors in ovarian cancer of the domestic hen. The hen is a good model because it develops ovarian cancer with a high spontaneous incidence. The specific aims of this study are to: 1) determine whether ovarian cancer in the hen is estrogen dependent; 2) determine if the estrogen receptor is differentially regulated in ovarian cancer; 3) characterize the non-nuclear estrogen receptor; and 4) determine downstream pathways associated with estrogen receptor mediated proliferation. These questions will be answered using a variety of molecular techniques including PCR, Western blot, immunohistochemistry and microarray analyses, in vitro methods including cell culture, ex vivo (or in ovo) methods including CAM grafts of normal and tumor ovarian tissue, and in vivo methods including treatment of hens with estradiol. Once these questions are answered, we will have a better understanding of the role of estrogen and its receptors in ovarian cancer. These answers will also allow us to understand the mechanism of estrogen action promoting the formation or proliferation of ovarian tumors in the hen, which may be correlated to the role estrogen and its receptors m,ay play in human ovarian cancer. Furthermore, understanding estrogen's actions might lead to possible treatment options that could be applicable to human disease. Relevance: Ovarian cancer is the fifth leading cause of cancer death among women. Estrogens may promote ovarian tumor initiation or proliferation; therefore, it is important to understand its role in the origin or progression of the disease.